Behavioral investigation of mice with experimental autoimmune encephalomyelitis / Investigação comportamental de camundongos com encefalomielite autoimune experimental

Multiple sclerosis is a neuroinflammatory disease that results in serious neurological disability. Besides physical impairment, behavioral symptoms are also common in patients with multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is considered to be a model of multiple sclerosis and mimics the main features of the disease, such as demyelination and motor impairment. In this work, we aimed to study behavioral parameters in animals with EAE using the MOG35-55 model in C57BL/6 mice. We analyzed memory and anxiety in animals using the elevated plus maze, the step down inhibitory avoidance task and the memory recognition test. No differences in any tests were found when comparing controls and animals induced with EAE. Therefore, we conclude that behavioral changes in animals with EAE induced with MOG35-55 are probably subtle or absent.

Esclerose múltipla é uma doença neuroinflamatória que resulta em séria incapacidade neurológica. Além do comprometimento físico, sintomas comportamentais também são comuns em pacientes com esclerose múltipla. A encefalomielite autoimune experimental (EAE) é considerada um modelo de esclerose múltipla e mimetiza as principais caracte-rísticas da doença, como a desmielinização e a fraqueza motora. Neste trabalho, objetivamos estudar parâmetros comportamentais em animais com EAE usando o modelo de MOG35-55 em camundongos C57BL/6. Analisamos memória e ansiedade em animais utilizando o labirinto em cruz elevado, o teste da esquiva inibitória e o teste de memória de reconhecimento. Nenhuma diferença em quaisquer dos testes foi encontrada comparando animais controles e animais induzidos com EAE. Assim, concluímos que alterações comportamentais em animais com EAE induzidos com MOG35-55 são provavelmente sutis ou ausentes.

Absence of PAF receptor alters cellular infiltrate but not rolling and adhesion of leukocytes in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a condition induced in some susceptible species to the study of multiple sclerosis (MS). The platelet activating factor (PAF) is an important mediator of immune responses and seems to be involved in MS. However, the participation of PAF in EAE and MS remains controversial. Thus, in this study, we aimed to evaluate the role of PAF receptor in the pathogenesis of EAE. EAE was induced using an emulsion containing MOG(35-55). EAE-induced PAF receptor knock out (PAFR(-/-)) mice presented milder disease when compared to C57BL/6 wild type (WT) animals. PAFR(-/-) animals had lower inflammatory infiltrates in central nervous system (CNS) tissue when compared to WT mice. However, intravital microscopy in cerebral microvasculature revealed similar levels of rolling and adhering leukocytes in both WT and PAFR(-/-) mice. Interleukine (IL)-17 and chemokines C-C motif legends (CCL)2 and CCL5 were significantly lower in PAFR(-/-) mice when compared to WT mice. Brain infiltrating cluster of differentiation (CD)4(+) leukocytes and IL-17(+) leukocytes was diminished in PAFR(-/-) when compared to WT mice. Taken together, our results suggest that PAF receptor is important in the induction and development of EAE, although it has no influence in rolling and adhesion steps of cell recruitment. The absence of PAF receptor results in milder disease by altering the type of inflammatory mediators and cells that are present in CNS tissue.

Behavioral investigation of mice with experimental autoimmune encephalomyelitis.

Multiple sclerosis is a neuroinflammatory disease that results in serious neurological disability. Besides physical impairment, behavioral symptoms are also common in patients with multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is considered to be a model of multiple sclerosis and mimics the main features of the disease, such as demyelination and motor impairment. In this work, we aimed to study behavioral parameters in animals with EAE using the MOG(35-55) model in C57BL/6 mice. We analyzed memory and anxiety in animals using the elevated plus maze, the step down inhibitory avoidance task and the memory recognition test. No differences in any tests were found when comparing controls and animals induced with EAE. Therefore, we conclude that behavioral changes in animals with EAE induced with MOG(35-55) are probably subtle or absent.

Absence of PI3Kgamma leads to increased leukocyte apoptosis and diminished severity of experimental autoimmune encephalomyelitis.

Phosphatidylinositol-3-kinase gamma (PI3Kgamma) plays an important role in the motility of leukocytes in several models of inflammation. In this work, the role of PI3Kgamma in experimental autoimmune encephalomyelitis (EAE) was investigated. EAE was induced in wild-type and PI3Kgamma deficient mice (PI3Kgamma(-)(/)(-)). WT animals had a peak of clinical symptoms around day 14 post-induction (p.i.). PI3Kgamma(-)(/)(-) animals developed milder EAE signs and peak of disease was noticed only on day 21 p.i. Better clinical outcome correlated with the absence of perivascular cuffs on day 14 p.i. and with decreased levels of CCL2 and CCL5 in brain of PI3Kgamma(-)(/)(-) mice. There was increased leukocyte rolling and adhesion in pial vessels, as assessed by intravital microscopy, at day 14 after EAE induction in WT mice. The latter parameters were unaltered in PI3Kgamma(-)(/)(-) mice subjected to EAE. Moreover, the PI3Kgamma inhibitor AS-605240 given just before the intravital microscopy failed to affect leukocyte rolling or adhesion. Finally, there was a significant increase in the number of apoptotic cells in the CNS of EAE-induced PI3Kgamma(-/-) mice. Our results suggest that PI3Kgamma is involved in EAE and plays a more important role in mediating leukocyte survival than leukocyte adhesion in this experimental model of multiple sclerosis.

Paracoccidioidomicose com comprometimento do sistema nervoso central: revisão sistemática da literatura / Paracoccidioidomycosis compromising the central nervous system: a systematic review of the literature

Este trabalho é o primeiro a realizar uma revisão sistemática dos casos de neuroparacoccidioidomicose disponíveis na literatura. Foram encontrados 257 casos em 81 trabalhos pesquisados pelo MEDLINE e LILACS, com maior número de publicações após as décadas de 1970-1980. Aproximadamente, 93 por cento dos pacientes eram homens, principalmente lavradores, com idade média de 43 anos. O quadro caracterizou-se por sintomatologia motora ou de hipertensão intracraniana. A forma crônica pseudotumoral predominou. O período médio de evolução foi de 4,9 meses. As lesões foram principalmente supratentoriais (66,8 por cento), localizando-se nos lobos frontais e parietais. A biópsia determinou o diagnóstico em 57,2 por cento dos casos e utilizaram-se métodos de neuroimagem em 64,6 por cento deles. Houve grande associação com a forma pulmonar da doença (59,1 por cento). A mortalidade foi de 44,1 por cento e 50,1 por cento dos sobreviventes evoluíram com sequelas, principalmente motoras. Assim, deve-se considerar a neuroparacoccidioidomicose no diagnóstico diferencial dos processos expansivos e meningoencefalíticos do sistema nervoso central para se estabelecer tratamento precoce e evitar seqüelas incapacitantes.

This study is the first systematic review of cases of neuroparacoccidioidomycosis available in the literature. Through searches in the MEDLINE and LILACS databases, 257 cases were found in 81 published studies, mainly after the 1970s-1980s. Approximately 93 percent of the patients were men, especially farm laborers, with a mean age of 43 years. The characteristic symptoms were motor deficits or intracranial hypertension. The chronic pseudotumoral form predominated. The mean period of evolution was 4.9 months. The lesions were mainly supratentorial (66.8 percent), located in the frontal and parietal lobes. The diagnosis was determined by biopsy in 57.2 percent of the cases and neuroimaging methods were used in 64.6 percent of them. A large proportion of the cases were associated with the pulmonary form of the disease (59.1 percent). The mortality rate was 44.1 percent, and 50.1 percent of the survivors developed sequelae, especially motor impairment. Thus, neuroparacoccidioidomycosis should be considered in the differential diagnosis for expansive and meningoencephalitic processes in the central nervous system, in order to establish early treatment and to avoid disabling sequelae.

Cerebrospinal fluid levels of chemokines in HIV infected patients with and without opportunistic infection of the central nervous system.

Chemokines are chemoattractant cytokines involved in the immune response of a wide variety of diseases. There are few studies assessing their role in opportunistic infections in HIV-infected patients. In this study, we measured CC and CXC chemokines in cerebrospinal fluid (CSF) samples obtained from 40 HIV-infected patients with or without opportunistic infections of the central nervous system (CNS). CSF samples were also analyzed for quantification of total protein, cell count and HIV-1 RNA. HIV+ patients with cryptococcal meningitis had higher levels of CCL2, CCL3, CCL5, CXCL9 and CXCL10 when compared to patients without opportunistic neurological infections. Furthermore, HIV+ patients with associated cryptococcal meningitis had higher levels of CCL3, CXCL9 and CXCL10 when compared to HIV+ patients with associated toxoplasmic encephalitis. CCL3 and CXCL9 levels were positively correlated with CSF HIV-1 RNA levels, CSF protein concentration, and CSF cell count. CXCL10 level was correlated with the CSF viral load and the CSF cell count and CCL5 level was correlated with the CSF cell count. In conclusion, the profile of chemokines in CSF of HIV patients may differ according to the modality of the presented opportunistic infection and according to other biological markers, such as viral load in CSF. These differences are probably related to different patterns of neuroinflammatory responses displayed by patients with different opportunistic neurological infections.

[Paracoccidioidomycosis compromising the central nervous system: a systematic review of the literature]. / Paracoccidioidomicose com comprometimento do sistema nervoso central: revisão sistemática da literatura.

This study is the first systematic review of cases of neuroparacoccidioidomycosis available in the literature. Through searches in the MEDLINE and LILACS databases, 257 cases were found in 81 published studies, mainly after the 1970s-1980s. Approximately 93% of the patients were men, especially farm laborers, with a mean age of 43 years. The characteristic symptoms were motor deficits or intracranial hypertension. The chronic pseudotumoral form predominated. The mean period of evolution was 4.9 months. The lesions were mainly supratentorial (66.8%), located in the frontal and parietal lobes. The diagnosis was determined by biopsy in 57.2% of the cases and neuroimaging methods were used in 64.6% of them. A large proportion of the cases were associated with the pulmonary form of the disease (59.1%). The mortality rate was 44.1%, and 50.1% of the survivors developed sequelae, especially motor impairment. Thus, neuroparacoccidioidomycosis should be considered in the differential diagnosis for expansive and meningoencephalitic processes in the central nervous system, in order to establish early treatment and to avoid disabling sequelae.

Paracoccidioidomicose com comprometimento do sistema nervoso central: revisão de literatura / Paracoccidioidomycose with central nervous systeminvolvement: review of the literature

A Paracoccidioidomicose (PCM), considerada a micose profunda mais importante da América Latina, é causada pelo fungo Paracoccidioides brasiliensis. O Brasil concentra o maior número de casos, especialmente na região Sudeste. A doença pode acometer inúmeros órgãos como os pulmões, a pele, as mucosas. O envolvimento do sistema nervoso central (SNC) ocorre em aproximadamente 10% dos casos e sua incidência pode ser subestimada devido à ocorrência de apresentações assintomáticas, avaliação neurológica inadequada, falta de testes específicos de neuroimagem e baixa freqüência de estudo do SNC em necrópsias. As formas de apresentação são a meníngea/meningoencefálica, raras, e a pseudotumoral, mais freqüente. A sintomatologia é diversa, variando conforme a localização das lesões, e não específica. Os métodos de neuroimagem são considerados essenciais no auxílio diagnóstico, o exame do líquor é pouco específico e métodos sorológicos ainda têm valor limitado, sendo usados principalmente para seguimento da resposta ao tratamento, cuja primeira escolha, para qualquer forma de apresentação, é a associação sulfametoxazoltrimetoprim. Reserva-se a anfotericina B para os casos de resistência ou intolerância às sulfonamidas. Uma alternativa são o azólicos, como o itraconazol ou o fluconazol. Ainda não se estabeleceram parâmetros confiáveis para indicar o momento seguro de interrupção do tratamento ou para sua reintrodução precoce em caso de recidivas. A PCM deve ter ser considerada no diagnóstico diferencial dos processos meningoencefalíticos e expansivos do SNC, dependendo de um alto grau de suspeição do médico a fim de se estabelecer o tratamento precoce e evitar o surgimento de seqüelas incapacitantes.

Paracoccidioidomycosis (PCM), considered the most important systemic mycosis in Latin America, is caused by the fungus Paracoccidioides brasiliensis. Brazil has the greatest amount of reported cases, especially in the Southeastern region. The disease can affect several sites as the lungs, the skin and the mucous membranes. Central nervous system (CNS) involvement occurs approximately in 10% of the cases, and its incidence can be underestimated due to the occurrence of asymptomatic cases, inadequate neurological evaluation, no specific neuroimagingexams, and low frequency of SNC investigation in autopsies. Neuroparacoccidioidomycosis (NPCM) comprises meningeal form, which is rare, and the most frequent pseudotumoral one. The symptoms are varied, depending on the location of the lesions, and not specific. Neuroimaging methods are considered essential for the diagnosis. Examination of the cerebral spinal fluid is not specific and serological methods still have limited value, being used mainly in the evaluation of treatment response. The first choice for PCM treatment is the association sulfamethoxazoletrimethoprim. Amphotericin B is reserved for the cases of resistance or intolerance to sulfonamides. Alternatively there are itraconazole or fluconazole. No trustworthy parameters were yet established to indicate the ideal moment for interrupting drug treatment or for its early reintroduction. NPCM must be considered in the differential diagnosis of the meningeal and the tumoral/expansive processes of the CNS, depending on a high suspicion level of the physician in order to establish the early treatment and to avoid the development of disabling sequelae.

Successful vaccination against Leishmania chagasi infection in BALB/c mice with freeze-thawed Leishmania antigen and Corynebacterium parvum.

This study evaluated the potential of a Leishmania antigen vaccine in protecting BALB/c mice against Leishmania chagasi. Mice received two subcutaneous doses of L. amazonensis vaccine with Corynebacterium parvum and subsequent boost was done without adjuvant. One week later, mice were challenged with L. chagasi. We observed that this vaccine caused a significant reduction in parasite load in liver and spleen and induced a high production of IFN-gamma and IL-4 by spleen cells from vaccinated mice in response to Leishmania antigen. Together, our data show that this vaccine is capable of inducing a Th1/Th2 response that is important to control parasite replication.